Amino acids in type 2 diabetes

Rationale: Recent research identified clusters of circulating branched-chain amino acids (BCAA), aromatic amino acids (AAA) and amino acid-derived short-chain acylcarnitines in insulin resistant humans, as risk factors in the development of type 2 diabetes. The elevated amino acid clusters may derive from elevated amino acid supply or incomplete amino acid catabolism. These findings shed new light in the aetiology of diabetes, which for long time was considered to be related only to disturbances in fat and glucose metabolism, underlying the development of insulin resistance and compromised mitochondrial function. Here, I propose the novel hypothesize that type 2 diabetes mellitus (T2DM) is linked to dysregulated amino acid metabolism, resulting in elevated clusters of BCAA, AAA and acylcarnitines causing insulin resistance. Furthermore, I hypothesize that impaired amino acid metabolism underlies impaired mitochondrial oxidative capacity in T2DM via diminished delivery and flux of amino acid-derived tricarboxylic acid cycle (TCA) intermediates.
Objective: The experiments presented in this project include metabolic profiling of amino acid metabolism-derived intermediates in plasma and muscle of patients with T2DM and in first-degree relatives (FDR), which has never been explored before.
Study design: The study presented is an observational study.
Study population: Ten male patients with T2DM, 10 FDR of patients with T2DM and 10 healthy, non-diabetic control participants will be enrolled into the study. Groups will be matched for age and BMI (age: 45-65 yrs; BMI: 27-35 kg/m2).
Main study parameters/endpoints: The main study objectives are i) to determine whether T2DM is related to impaired BCAA metabolism (umol kg-1 min-1) in muscle.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The risk on hematomas and inflammation upon taking muscle biopsies is low as sterile material and pressure bandage will be used. Participants will not have a direct benefit from the dietary intervention. The burden of the diet, the risks of the performed measurements and the physical discomfort are relatively low.

We hypothesize that patients with type 2 diabetes and first-degree realtives of patients with type 2 diabetes are characterized with a diminished branched-chain amino acid oxidative capacity

n= 2 weeks, including 3 visits (including screening)